tbuckley/cabot-search huggingface dataset:
Abstract 3250: Microbial metabolite, Urolithin A acts as chemo-sensitizing adjuvant in conventional drug therapies via modulation of drug transporters and EMT markers
Authors: Sweta Ghosh, Rajbir Singh, Zachary M. Vanwinkle, Haixun Guo, Praveen K. Vemula, Ajay Goel, Bodduluri Haribabu, Venkatakrishna Rao Jala
Journal: Cancer Research (2022)

Abstract Colon cancer is the third leading cause in cancer related deaths in United States of America. Chemoresistance (drug resistance) of tumors is the primary reason for the failure of chemotherapy and a major cause of mortality in colon cancer. The molecular mechanisms involved in chemoresistance or methods to chemosensitization of cancer cells to chemotherapy remain elusive. Recent studies suggest that gut microbiota and microbial metabolites play a crucial role in the development and progression of colon cancer. Urolithin A (UroA) is a gut microbial metabolite derived from ellagitannin/ellagic acid rich-diets such as pomegranate and berries. Here, we identified that UroA and its novel structural analogue (UAS03) chemosensitize 5FU resistant (5FUR) colon cancer cells to 5FU treatment. Our data suggested that combination of 5FU with UroA or UAS03 significantly reduced cell viability of 5FUR colon cancer cell lines with combination index (CI) less than 1 suggesting their synergism. Moreover, UroA or UAS03 in combination with 5FU significantly inhibited 5FUR colon cancer cell proliferation, migration as well as induced apoptosis. Mechanistically, UroA or UAS03 treatment down regulated drug transporters (MDR1, BCRP and MRP2) leading to decreased efflux of drug (e.g., 5FU) and potentially responsible for chemosensitization. Furthermore, treatment with these compounds also modulated EMT makers (e.g., downregulated Snail and β-catenin; upregulated ZO-1 and E-cadherin) to reduce EMT transition. Treatment of UroA or UAS03 in combination with 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Taken together, utilization of UroA or UAS03 in combination with 5FU treatment may provide better therapeutic options for 5FUR colon cancer alleviation. Citation Format: Sweta Ghosh, Rajbir Singh, Zachary M. Vanwinkle, Haixun Guo, Praveen K. Vemula, Ajay Goel, Bodduluri Haribabu, Venkatakrishna Rao Jala. Microbial metabolite, Urolithin A acts as chemo-sensitizing adjuvant in conventional drug therapies via modulation of drug transporters and EMT markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3250.
Abstract 340: The Hu2G10 tumor-selective anti-Trop-2 monoclonal antibody targets the cleaved-activated Trop-2 and shows therapeutic efficacy against multiple human cancers
Authors: Saverio Alberti, Marco Trerotola, Emanuela Guerra
Journal: Cancer Research (2022)

Abstract Trop-2 is a transmembrane glycoprotein that transduces a calcium signal and activates growth-signaling networks that converge on Akt, ERK, Cyclin D1, NFkB (1). We discovered that Trop-2 cleavage by ADAM10 is an activator switch for induction of cancer growth and metastatic diffusion (2). This cleavage causes a spatial rearrangement of the extracellular portion of Trop-2 and exposes protein sites that would normally be inaccessible.We devised a strategy to obtain monoclonal antibodies (mAbs) capable of recognizing these cancer-exposed sites.Most Trop-2-targeted approaches are based on anti-Trop-2 mAbs that recognize a single immunodominant epitope poised between the globular and stem regions. Such mAbs have limited therapeutic index.We removed the immunodominant epitope by deletion mutagenesis. To optimize breadth of immune response, mice were immunized with target proteins produced in cells with different end-glycosylation patterns, including tumor cells, insect, yeast, bacterial cells. Screening for cancer-specific mAbs were performed by cell-based ELISA assays, ELISA assays on recombinant target proteins, bio-layer interferometry, flow cytometry and fluorescence microscopy on cleaved, wild-type and glycosylation-site mutagenized Trop-2. mAbs were obtained that efficiently bound Trop-2 expressing cancer cells and were able to inhibit cell growth in vitro. We humanized the 2G10 mAb as the IgG1 Hu2G10 antibody with an affinity for recombinant, cancer-specific, cleaved Trop-2 that is several orders of magnitude higher than for the wtTrop-2. In vivo the naked Hu2G10 antibody was effective at inhibiting the growth of breast, colon, ovary and prostate cancers. In the ADC setting Hu2G10 drove high anticancer effectiveness with unprecedented specificity, for best-in-class anticancer therapy. (1) E. Guerra et al., The Trop-2 signalling network in cancer growth. Oncogene 32, 1594-1600 (2013).(2) M. Trerotola et al., Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23, 415-428 (2021). Citation Format: Saverio Alberti, Marco Trerotola, Emanuela Guerra. The Hu2G10 tumor-selective anti-Trop-2 monoclonal antibody targets the cleaved-activated Trop-2 and shows therapeutic efficacy against multiple human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 340.
Abstract 5325: Image-based functional precision medicine for repurposing neuroactive drugs in glioblastoma
Authors: Sohyon Lee, Tobias Weiss, Marcel Bühler, Rebekka Wegmann, Julien Mena, Michel Bihl, Sandra Goetze, Audrey van Drogen, Elisabeth J. Rushing, Bernd Wollscheid, Michael Weller, Berend Snijder
Journal: Cancer Research (2022)

Abstract Treatment of glioblastoma multiforme (GBM), the most aggressive form of primary brain cancer, has essentially not advanced over the past few decades. Numerous challenges hinder the successful development of new therapies, including drug delivery across the blood-brain barrier (BBB), the complexity of the tumor microenvironment (TME), and the lack of clinically predictive cancer models. Here, we present the results of an image-based ex vivo drug-testing platform that addresses these therapeutic roadblocks. To demonstrate the clinical utility of our platform, in a retrospective cohort of 14 GBM patients, we show that ex vivo sensitivity to Temozolomide (TMZ, 1st-line GBM chemotherapy), is associated with longer progression free survival (PFS) and overall survival (OS). Next, by screening 150 clinically approved drugs across 27 GBM surgical patient samples, we identify a set of BBB-permeable neuroactive drugs with anti-glioma activity. These neurological drugs display remarkably consistent on-target killing of cancer cells with minimal toxicity to non-malignant TME cells across both primary and recurrent GBM samples. Single-cell transcriptional profiling of GBM patient samples and functional genetics reveals novel glioma-dependencies on neurological drug-target expression. Furthermore, a drug-target network enrichment analysis uncovers an AP1/BTG/TP53 gene signature associated with the anti-glioma activity of neurological drugs. In silico screening of over 1 million compounds for this common gene signature identified additional drug hits that could be validated in patient samples with 90% accuracy. Multiplexed transcriptomics revealed AP-1 transcription factor family activation to be the common underlying feature of neurological drugs with anti-glioma activity. Among the most promising candidate drugs, we identify the atypical antidepressant Vortioxetine as the strongest inducer of this gene signature, and confirm its efficacy in vivo across multiple mouse models. Vortioxetine in combination with Temozolomide or Lomustine further increased median survival in vivo compared to single agents alone. This study thus provides a clinically predictive and personalized drug-testing platform that identifies new treatment opportunities for GBM, warranting further investigation. Citation Format: Sohyon Lee, Tobias Weiss, Marcel Bühler, Rebekka Wegmann, Julien Mena, Michel Bihl, Sandra Goetze, Audrey van Drogen, Elisabeth J. Rushing, Bernd Wollscheid, Michael Weller, Berend Snijder. Image-based functional precision medicine for repurposing neuroactive drugs in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5325.
Abstract 5884: Comprehensive analyzing the expression of IDO1 and TDO2 in bladder cancer
Authors: Quoc Thang Pham, Thanh Tu Nguyen, Thao Quyen Nguyen, Duc Tung Luu, Thi Nhu Diem Pham, Thi Thanh Tam Bui, Thanh Tu Duong, Dang Anh Thu Phan, Quoc Dat Ngo
Journal: Cancer Research (2022)

Abstract Background: Several lines of evidence have been focused on the roles of tryptophan metabolism genes like indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) in bladder cancer progression. However, the alternative way of targeting in cancer immunotherapy has been not yet investigated in bladder cancer. Method: We explored and validated the clinicopathological significance and the correlation with immune infiltrates of IDO1 and TDO2 expression in bladder cancer using Bladder urothelial carcinoma (BLCA) and other Gene Expression Omnibus (GEO) datasets (GSE13570, GSE31684, GSE48277) downloaded from https://xenabrowser.net/ and https://www.ncbi.nlm.nih.gov/geo/. The correlation between IDO1, TDO2 expression and the immune infiltrates as well as PD-L1 gene expression in BLCA dataset was explored with TIMER2.0, http://timer.comp-genomics.org/. Immunohistochemistry was performed to validate the relationship between TDO2 and PD-L1 expression in bladder cancer. Results: We figured out the IDO1 and TDO2 expressions were significantly upregulated in basal type compared with other molecular subtypes in BLCA. P53 mutations were associated with upregulation of IDO1 and TDO2 expression (p&amp;lt;0.01) whereas FGFR3 mutation was associated with downregulation of IDO1 and TDO2 expression (p&amp;lt;0.001). The overexpression of IDO1, TDO2 overexpression was significantly associated with advanced disease in BC. IDO1 and TDO2 expression were significantly correlated with purity and immune cell infiltrates, including T cells CD8+, T cells CD4+, B cells, neutrophils, and macrophages as wells as myeloid dendritic cells. Interestingly, TDO2 were positively correlated with cancer-associated fibroblasts (CAFs) (rho=0.5, p=1.14e-24). PD-L1 expression was also correlated with IDO1 (rho=0.64, p=4.42e-49) and TDO2 expression (rho=0.42, p=5.01e-19). Immunohistochemistry revealed the correlation between TDO2 and PD-L1 expression (p=0.011). Conclusion: Our results pointed out that IDO1 and TDO2 could play an essential role in regulating the tumor microenvironment as well as immune tolerance in bladder cancer. Suggesting that IDO1, TDO2 might be a promising novel immunotherapy target for bladder cancer patients. Citation Format: Quoc Thang Pham, Thanh Tu Nguyen, Thao Quyen Nguyen, Duc Tung Luu, Thi Nhu Diem Pham, Thi Thanh Tam Bui, Thanh Tu Duong, Dang Anh Thu Phan, Quoc Dat Ngo. Comprehensive analyzing the expression of IDO1 and TDO2 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5884.
Abstract 3654: Development and application of the iHELP platform to facilitate the establishment of healthy habits for the prevention of pancreatic cancer
Authors: Temin Ke, I HELP, Artitaya Lophatananon, Marzena Nieroda, Kenneth Muir
Journal: Cancer Research (2022)

Abstract Background: Pancreatic cancer is the 7 th leading cause of cancer-related mortality and the 12 th most common cancer globally. The survival rate from pancreatic cancer is very poor so prevention and early detection approaches are important. It is estimated that 37% of pancreatic cancer cases can be prevented. Despite advanced knowledge on risk factors, prevention by personalized approach remain to be explored. The iHelp platform is being developed based on combining people’s risk factors and can be used as a tool to help people develop new health habits. Study aim: To further develop and evaluate the i-Help risk assessment and support platform that utilizes big data management and Artificial Intelligence (AI) approaches to establish person-centric early risk prediction, prevention, and intervention measures. Study design: The iHelp platform is an AI-based Scalable Big Data Platform which provides the necessary performance and features for the management and analysis of the heterogeneous data. The data source are derived from various sources including patients’ historical medical data as well as self-reported lifestyle habits and behaviors, social media interactions, integrated in the form of a Holistic Health Record (HHRs). Through the utilization of the iHelp platform we are implementing innovative AI algorithms and techniques to accomplish multi-modal causal analysis, real-time anomaly detection to estimate risk prediction, forecasting of risk trajectories, and detection of suggested behavioral changes. AI techniques will draw adaptive learning models that provide the decision support based on the risk predictions as well as personalized prevention and intervention measures. Users of the platform are supported to make appropriate lifestyle changes and monitored by using mobile or wearable devices. Results: We will present the design of the platform together with feedback from end users on key modules. Ultimately we propose that the outcomes of iHelp components will not only integrate data from multiple sources, but they will also provide informative and motivational individualized pancreatic cancer risk reduction recommendations. Citation Format: Temin Ke, I HELP, Artitaya Lophatananon, Marzena Nieroda, Kenneth Muir. Development and application of the iHELP platform to facilitate the establishment of healthy habits for the prevention of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3654.
Abstract 2858: Development of a first-in-class humanized antibody targeting CXCL1 in bladder cancer
Authors: Kaoru Murakami, Yuka Sasaki, Hideki Furuya, Charles Rosser
Journal: Cancer Research (2022)

Abstract Introduction and Objectives: Chemokine (C-X-C motif) ligand 1 (CXCL1) plays a crucial role in tumor initiation, promotion, and progression in bladder cancer (BCa) development. Previously, we reported on a monoclonal murine antibody (HL2401) towards CXCL1 which was capable of inhibiting growth in both in vitro and in vivo models. Herein, we have developed a first-in-class humanized monoclonal antibody neutralizing CXCL1 (NTC-001). This study is final step in pre-clinical stage. In this study, we aimed to evaluate efficacy and safety of the antibody to move into phase 1 clinical trials in near future. Methods: We humanized mouse anti-human CXCL1 antibody resulting in NTC-001, and then tested for the following: molecular weight and pH, specificity, binding affinity to ligand and to albumin, ability to inhibit in vitro angiogenesis, ability to inhibit cellular proliferation alone or with chemotherapy, and pharmacokinetics and pharmacodynamics. Results: NTC-001 had a molecular weight of 150kD, and was an acidic antibody (pH5.1). NTC-001 specifically bound human CXCL1 in both WB and ELISA. NTC-001 was bound to albumin and had minimal hepatic metabolism. NTC-001 significantly inhibited tube formation in HUVEC, and more efficiently with the formulation. NTC-001 significantly inhibited T24 cell proliferation (p&amp;lt;0.001). Inhibitory effect of NTC-001 on cell proliferation was correlated with the levels of CXCL1 expression in BCa cell lines. Compared to CXCL1 expression-low group (RT112 and UMUC-14), CXCL1 expression-high group (T24, 5637, 253J, 253J-BV) tended to show low IC50. Synergistic combination efficacy was observed in NTC-001 in combination with gemcitabine (combination index&amp;lt;1) though not with cisplatin. PK study demonstrated a half-life of 324 hours and 18 hours in CD-1 and NSG-SGM3, respectively. Conclusions: NTC-001 is a first in class humanized neutralizing monoclonal antibody towards CXCL1, and could be a promising therapeutic agent in BCa. We are going to proceed to complete our investigational new drug enabling studies in both small and large animals. Citation Format: Kaoru Murakami, Yuka Sasaki, Hideki Furuya, Charles Rosser. Development of a first-in-class humanized antibody targeting CXCL1 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2858.
Abstract 636: Prediction of therapeutic response via data-driven maps of tumor cell architecture
Authors: Erica N. Silva, Akshat Singhal, Sungjoon Park, Jason Kreisberg, Trey Ideker
Journal: Cancer Research (2022)

Abstract Machine learning is revolutionizing the analysis of biological and biomedical data. One continued challenge is to build models that are not only predictive but also provide mechanistic explanations. Directly incorporating explainability into the model’s design has emerged as a possible solution. Recently, we reported several “visible” machine learning systems - DCell and DrugCell - which predict cellular growth based on genetic perturbations. In these visible models, the structure of the underlying neural network mirrors known aspects of cell biology. Here we designed a cancer-specific model of therapeutic response. First, we selected NeST (Nested Systems in Tumors; Zheng et al., Science 2021), a data-driven hierarchy of tumor cell systems under selection in cancer, as the structure for our visible neural network. Second, we restricted input features to genes currently assayed on clinical cancer gene panels. We considered training schemes that assess the model’s ability to generalize to novel genotypes. Most importantly, we assessed performance on patient data from the AACR Project GENIE clinical trial where we discriminated between patients who are likely to respond to selected drug treatments. Finally, we examined model explanations within the visible NeST architecture to highlight cellular mechanisms of response to drug therapy. Overall, we found that by considering a tumor cell architecture optimized for clinical application, we can design an interpretable deep learning model that both accurately stratifies patient responses and explains the drug mechanism in cancer cells. Citation Format: Erica N. Silva, Akshat Singhal, Sungjoon Park, Jason Kreisberg, Trey Ideker. Prediction of therapeutic response via data-driven maps of tumor cell architecture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 636.
Features of the mucous barrier in functional bowel diseases and ulcerative colitis
Authors: A.E. Dorofeyev, S.M. Tkach, О.О. Dyadyk, V.M. Prikhodko
Journal: GASTROENTEROLOGY (2022)

Background. The intestinal mucosal barrier may change under the influence of exogenous and endogenous factors. Changes in its physical and chemical characteristics are observed in patients with gastrointestinal diseases, such as irritable bowel syndrome, ulcerative colitis, Crohn’s disease, and with other pathologies, such as diabetes mellitus, food allergies, rheumatoid arthritis, etc. Also, the permeability of the intestinal wall was influenced by tight junctions, which are weakened due to eating disorders, psycho-emotional factors, and chemical agents. The purpose of the study was evaluating of changes in the mucosal barrier in patients with functional and inflammatory bowel diseases. Materials and methods. 270 patients with different subtypes of irritable bowel syndrome and 218 patients with ulcerative colitis were examined. Colonoscopy followed by a morphological assessment of biopsy specimens and immunohistochemical studies using markers of claudin 1 and 7, mucins 1, 2, 3, 4, 5AC, and trefoil factors 1–3 was performed in all patients. Results. A decrease in the level of tight junction proteins called claudins was observed in patients with functional bowel disease. Patients with irritable bowel syndrome associated with diarrhea had a lower level of claudin-1 only, while patients with mixed form had also a lower level of claudin-7. A decrease in the level of both secretory and membrane-bound mucins and an increase in the level of the trefoil factors were observed at the same time among the patients with ulcerative colitis which may indicate a dysregulation and a violation of the protective function of mucus. Conclusions. The pathogenesis of a violation of the protective function of the mucosa of functional and inflammatory bowel disease is different, which may determine approaches to the treatment of patients with such pathologies.
Abstract 3308: Chemoradiation sensitization effect of PARPi in non-small cell lung cancer
Authors: Rui Ye, Kaile Wang, Yawei Qiao, Zhenna Xiao, Yun Yan, Jianzhong He, Nan Li, Yifan Wang, Min Hu, Shanshan Bai, Emi Sei, Nicholas Navin, Steven Lin
Journal: Cancer Research (2022)

Abstract Chemoradiation (CRT) is widely used to treat locally advanced non-small cell lung cancer (NSCLC) patients, but only around 30% of patients achieve pathological complete response. Here, we utilized an in vitro high-content clonogenic survival screening method to identify CRT sensitizers from the NCI Cancer Therapy Evaluation Program (CTEP) portfolio. Talazoparib (PARPi) was identified among the top candidates to show potent CRT sensitization effects in both KRAS mutant and TP53 mutant NCSLC cell lines. We validated the CRT sensitization effect of PARPi on lung tumors in vivo with cell line xenografts mouse models. To further investigate alterations in the tumor microenvironment (TME) induced by PARPi, we utilized syngeneic mouse models and showed that the combination of radiotherapy, PARPi, and PD-L1 blockade achieved superior tumor control effects. By applying single cell RNA sequencing technologies to the mouse tumors, we found that PARPi combined with CRT or immunotherapy significantly reprogrammed the tumor cells and TME, resulting in the increase of tumor-infiltrating T cells which elicit potent tumor control effects. Our data showed that PARPi sensitizes NSCLC tumors to CRT and immunotherapy through a combination of tumor-intrinsic and extrinsic phenomenon. Citation Format: Rui Ye, Kaile Wang, Yawei Qiao, Zhenna Xiao, Yun Yan, Jianzhong He, Nan Li, Yifan Wang, Min Hu, Shanshan Bai, Emi Sei, Nicholas Navin, Steven Lin. Chemoradiation sensitization effect of PARPi in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3308.